DESCRIPTION: Chronic and degenerative diseases result in organ or tissue deterioration over time and are the leading cause of death and disability in the United States. Stem cells have the capacity to restore function to damaged tissues and have been used in a wide range of pre-clinical models to promote tissue repair. However, clinical translation of these therapies has been complicated by issues associated with cell isolation, ex vivo manipulation, and transplantation. In vivo generation of induced pluripotent stem cells (iPSCs) would circumvent these limitations. Studies have demonstrated that tissue microenvironments can support in vivo reprogramming and transdifferentiation, but in vivo generation of iPSCs within a specific tissue environment has not been attempted to date. In this study we will develop an efficient method for reprogramming cells in vivo using a combination of the micro RNA cluster miR302/367 for cellular reprogramming and minicircle DNA for gene delivery. Three key factors will be addressed: 1) efficiency of in vivo reprogramming (Aim I), 2) pluripotency state of the in vivo generated iPSCs (Aim II), and 3) documentation of off target effects associated with reprogramming (Aim III). We believe that generating iPSCs in vivo is a viable alternative to traditional stem cell therapies. Developing an efficient method for tissue specific in vivo reprogramming lays the necessary foundation for designing regenerative therapies with a broad range of applications.